Catalytic inhibitor of Protein Phosphatase 5 activates the extrinsic apoptotic pathway by disrupting complex II in kidney cancer

Elham F. Ahanin, Rebecca A. Sager, Sarah J. Backe, Diana M. Dunn, Natela Dushukyan, Adam R. Blanden, Nilamber A. Mate, Tamie Suzuki, Tyler Anderson, Merin Roy, Jasmeen Oberoi, Chrisostomos Prodromou, Imad Nsouli, Michael Daneshvar, Gennady Bratslavsky, Mark R. Woodford, Dimitra Bourboulia, John D. Chisholm, Mehdi Mollapour

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Serine/threonine protein phosphatase-5 (PP5) is involved in tumor progression and survival, making it an attractive therapeutic target. Specific inhibition of protein phosphatases has remained challenging because of their conserved catalytic sites. PP5 contains its regulatory domains within a single polypeptide chain, making it a more desirable target. Here we used an in silico approach to screen and develop a selective inhibitor of PP5. Compound P053 is a competitive inhibitor of PP5 that binds to its catalytic domain and causes apoptosis in renal cancer. We further demonstrated that PP5 interacts with FADD, RIPK1, and caspase 8, components of the extrinsic apoptotic pathway complex II. Specifically, PP5 dephosphorylates and inactivates the death effector protein FADD, preserving complex II integrity and regulating extrinsic apoptosis. Our data suggests that PP5 promotes renal cancer survival by suppressing the extrinsic apoptotic pathway. Pharmacologic inhibition of PP5 activates this pathway, presenting a viable therapeutic strategy for renal cancer.

Original languageEnglish (US)
Pages (from-to)1223-1234.e12
JournalCell Chemical Biology
Volume30
Issue number10
DOIs
StatePublished - Oct 19 2023

Keywords

  • FADD
  • clear cell renal cell carcinoma
  • co-chaperone
  • extrinsic apoptotic pathway
  • heat shock protein-90
  • molecular chaperone
  • serine/threonine phosphatase-5

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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